Polymeric hydrogels are well known in the art and can be defined as two- or multicomponent systems consisting of a three-dimensional network of polymer chains and water that fills the space between macromolecules. A hydrogel is a network of polymer chains that are water-insoluble, sometimes found as a colloidal gel in which water is the dispersion medium. Hydrogels are superabsorbent (they can contain over 99% water) natural or synthetic polymers. Hydrogels possess also a degree of flexibility very similar to natural tissue, due to their significant water content.
Hydrogels are commonly used in soft contact lenses, wound dressings, drug-delivery systems, superabsorbents, a number of medical and regenerative medicine applications. Depending on the properties of the polymer (polymers) used, as well as on the nature and density of the network joints, such structures in an equilibrium can contain various amounts of water; typically in the swollen state the mass fraction of water in a hydrogel is much higher than the mass fraction of polymer.
Two general classes of hydrogels have been defined. The first are physical hydrogels, where the chains are connected by electrostatic forces, hydrogen bonds, hydrophobic interactions or chain entanglements (such gels are non-permanent and usually they can be converted to polymer solutions by heating). Physical cross-linking of polymer chains can be achieved using a variety of environmental triggers (pH, temperature, ionic strength) and a variety of physicochemical interactions (hydrophobic interactions, charge condensation, hydrogen bonding, or supramolecular interactions). The presence of reversible crosslinking points in physically crosslinked hydrogels allows solvent casting and/or thermal processing. The major disadvantage of physically crosslinked hydrogels, however, is their weak mechanical properties in the swollen state and the range of materials that can be triggered to form in physiologically relevant conditions are extremely limited.
The second class of hydrogels is chemical hydrogels, which generally have covalent bonds linking the chains. Chemical methods include various click reactions, thiolene additions, metal-catalyzed azide-alkyne cycloadditions, Michael additions and Diels-Alder reactions. Metal-free, strain-promoted azide-alkyne “click” cycloaddition reactions have been applied to cell imaging as well as hydrogels systems due to its highly efficient conversion, orthogonality, and bio-friendly characteristics. The gel formation process is atom neutral in that there are not residuals that contaminate the system and could pose toxicity problems to associated biological systems
The onset of gel formation in these systems has typically been dependent on chemical or photochemical processes to initiate network formation from monomeric precursors. The use of bioincompatible initiating systems (such as chemical catalysts, heat, and/or ultraviolet (UV) light), and the presence of residual metal catalysts, organic solvents, and the incomplete conversion of the functional groups often lead to biocompatibility problems with these systems. The experimental demands for each of these gelation and functionalization strategies places distinct constraints on the utility and versatility of the respective hydrogels and make direct clinical translation difficult or impossible.
More recently, injectable hydrogels that form in situ have been found to hold additional promise, as they are adaptable to complicated defect sites relative to preformed hydrogels. In these systems, one or more solutions containing the constituent monomers of the hydrogel are injected or otherwise delivered to the site where the hydrogel is to be used and crosslinking is initiated. A common problem with these systems is that the photochemical, heat, UV light, and or chemical catalyst based initiators required for crosslinking of the polymer network are often not very biocompatible and do not work with sensitive cell types. Moreover, all of the byproducts of the crosslinking reaction must also be biocompatible and the presence of residual metal catalysts, organic solvents, and the incomplete conversion of the functional groups often lead to biocompatibility problems with these systems
In-situ forming hydrogels that are initiated by physical strain have also been developed. Many of these systems, however, will not crosslink in the presence of gelatins, collagens, lipids, carbohydrates or polymer nanofibers, significantly limiting their usefulness.
Accordingly, what is needed in the art is a hydrogel that is capable of being formed in situ (and in vivo), has no toxic byproducts, permits mechanical control of when (and where) cross linking occurs, is easier to use than heat based systems, and will cross link in the presence of gelatins, collagens, lipids, carbohydrates or polymer nanofibers.